1-halo-2-(n-acylcarbamyloxy)-3-aryloxy propanes



United States Patent 7 Claims. (Cl. 266-482) This application is a divisional application of application Serial No. 24,250, filed April 25, 1960, now Patent No. 3,168,525.

The present invention relates to processes involving the seriatim acylation and cyclization of substituted carbamyloxy propanes to form substituted oxazolidones and to certain intermediate compositions resulting from the acylation step.

The class of compounds identified as S-(substitutedmethyl)-2-oxazolidones, with a wide variety of -substituent organic radicals, is known in the art as a group of substances useful per se and as intermediates for making RCH CH(OH)CH NH amino-alcohols and their corresponding beta-halo amines by known prooedures.

In its process aspect, the present invention resides in the concept of making certain 5-(substituted-methyl)-2- oxazolidones, by reacting a l-halo-Z-carbamyloxy-S-substituted propane with an acylating agent to produce a l-halo-Z-(N-acylcarbamyloxy)-2-substituted propane and cyclizing said propane. In its composition aspect, the present invention resides in the concept of l-halo-Z-(N- acylcarbamyloxy) -3-substituted propanes wherein the 3-snbstituent is a cyclic organic ether radical attached through the oxygen atom. Since the acyl radical of the acylating agent is a non-functional group and does not aliect the course of the reaction, any substance commonly employed as an acylating agent can be used in the process, although agents having from one to ten carbon atoms in the acyl moiety are preferred because of present availability and economy. In View of the fact certain of the acylated chloro intermediates are herein claimed, it is specifically mentioned that all four halogens are equiv alent in the process and that the cyclic organic radical is an aryloxy or arylthio radical of the benzene and naphthalene ether series, whether unsubstituted or substituted by one or more low molecular weight moieties such as lower-alkyl, lower-alkoxy, halo, nitro, amino and trifluoromethyl. It is seen that the nature of the 3-511!)- stituent on the starting propane determines the nature of the 5-substituent in the oxazolidone prepared by the instant process.

In carrying out the acylation step of the process, the 1-halo-2-carbamyloxy-3substituted propane is mixed with an acylating agent and, desirably, an acid catalyst. The mixture is heated, preferably, on a steam bath and then under reflux until the reaction is substantially complete and the 1-halo-2-(N-acylcarbamyloxy)-3-substituted propane is recovered from the crude reaction product, or employed directly without purification or recovery, as the starting material following cyclization step. Among the acid catalysts which can be used are mineral acids as sulfuric, hydrochloric; organic acids as p-toluenesulionic; and other Lewis acids commonly known by chemists to promote acylation of the amino group. The acylating agents of choice are the lower alkanoic acid chlorides and anhydrides.

In carrying out the cyclization step of the process, the 1-halo-2- (N-acylcarbamyloxy) -3-substituted propane can be cyclized directly to yield the final product, a S-substituted-methyl-2-oxazolidone by reaction with a strong alkali, such as sodium hydroxide, potassium hydroxide, et cetera, at a temperature ranging from room temperature to about or degrees centigrade. Care must be taken to avoid maintaining the reaction mixture too long at the elevated temperature, to avoid decomposition of the S-substituted-methyl-Z-oxazolidone.

Alternatively, the cyclization step of the process can be carried out by reacting a mild alkali, such as sodium carbonate, potassium carbonate, or ammonium hydroxide, with the 1-ha'lo-2-(N-acylcarbamyloxy)-3-substituted propane to obtain a mixture of the final product, the 5-snbstituted-methyl-2-oxazolidone and an intermediate 5-substituted-rnethyl-3-acyl-2-oxazolidone. The intermediate 5-substituted-methyl-3-acyl-2-oxazolidone can be separated from the final product and separately hydrolyzcd with alkali to produce an additional quantity of the final product, the 5-substituted-methyl-2-oxazolidone.

The starting materials for conducting the process of the invention, that is, the 1-halo-2-carbamyloXy-3-substituted propanes can be prepared as follows: The appropriate 3-substituted-l,2-propanediol is condensed with a carbonic acid ester (R CO to form the corresponding 4-substituted-2-dioxolone. Processes for carrying out this reaction are disclosed, for example, in United States Patents 2,770,649 and 2,813,104. Next, the 4-substituted-2- dioxolone is ammonolyzed with ammonia in a solvent to yield a mixture of two isomers, a l-hydroxy-Z-carbarnyloxy-fr-substituted propane and a 1-carbamyloXy-2- hydroxy-3-substituted propane. This mixture results because the dioxolone ring opens at different positions upon ammonolysis. The isomers can be separated by tractional crystallization. The procedures for carrying out this ammonolysis are disclosed in Baizer et al. in the Journal of Organic Chemistry, volume 22, pages 1595 to 1599 (1957).

Where a 1-chloro-2-carbamyloxy-3substituted propane is desired as the starting material for the process of the invention, the isomeric mixture, obtained as outlined in the previous paragraph, can, Without separation of isorners, be treated with thionyl chloride to produce chlorination of the 1-hydroxy-2-carbamyloxy-propane and both chlorination and rearrangement of the l-carbamyloxy-2 hydroxy-propane and yield the l-chloro-Z-carbamyloxy-propane. Procedures for carrying out this process are also disclosed in the above-mentioned Baizer et :al. paper.

Throughout the specification, where the word percent is used alone, this means percent by Weight.

The following examples illustrate physical embodiments of the inventive concepts:

EXAMPLE 1 Conversion 0 I-chloro 2 carbamyloxyd-(0-meth0xyphenoxy) propane to 5 -(0 methoxyphenoxymelhyl)-2 oxazolidone Prepare the starting material, l-chloro-Z-carbamyloxy- 3-(o-methoxyphenoxy)propane as follows:

Melt 99 grams of 1,2 dihydroxy 3 (o-methoxyphenoxy)propane. Add 1.4 grams of sodium methoxide and 113 grams of dry diethyl carbonate to the melt. Distill out the ethanol formed by the ester inter-change reaction until the inside temperature of the reaction mixture reaches 120 degrees centigrade. Then add 1.5 grams of ammonium chloride and recover the excess diethyl carbonate by vacuum distillation. The residue contains 4- (o-methoxyphenoxymethyl)dioxolone melting at 68.4- 69.0 degrees centigrade. While stirring, add milliliters of isopropyl alcohol to the residue. Next add a solution of 17 grams of ammonia gas in 500 milliliters of isopropyl alcohol. Close the system and continue stirring residue. Add 400 milliliters of toluene to dissolve the residue. Next add 65 grams of thionyl chloride to the solution. Warm the mixture to 50 degrees centigrade and commence bubbling dry air through the mixture to sweep out gases. While continuing the bubbling of air,

raise the temperature to 80-85 degrees centigrade and maintain it there for two hours. Remove part of the toluene by distillation. Cool the solution with the formation of a precipitate. Filter the precipitate. Concentrate the filtrate by removing toluene by distillation. C-oolthe concentrated filtrate with the resultant formation of asecnd precipitate. Filter the second precipitate and combine it with the first precipitate to obtain a total of 104.5 grams of 1 chloro 2 carbamyloxy 3-(o-methoxyphenoxy)propane (80.7 percent yield).

Carry out the acylation and cyclization of the invention as follows: Mix one part of 1-chloro-2-carbamyloxy- 3-(omethoxyphenoxy)propane, prepared above, with a molar excess of acetic anhydride and a catalytic quantity of p-toluenesulfonic acid. Heat the mixture on a steam bath for one hour. Thereafter, while heating the mixture to maintain it under reflux, add alcohol. The mixture dissolves in the alcohol. Next, while maintaining the solution at about 70 degrees centigrade, add sodium hy-' droxide. A precipitate forms shortly after the completion of'the addition of the sodium hydroxide. Stir and cool the mixture for one hour. Filter and dry the precipitate t-o obtain 5 (o methoxyphenoxymethyl)-2-oxazo1idone melting 140-145 degrees centigrade.

EXAMPLE 2 Preparation of 5-(o-methoxyphenoxymerhyl)-2-oxazolidone with isolation of the intermediate l-chloro-Z-(N- acetylcarbamyloxy 3- (o-methoxy'phenoxy propane Dissolve 5 grams of 1 chloro 2 carbamyloxy- 3-(0- methoxyphenoxy)propane and 0.2 gram of p-toluenesulfonic acid in 40 milliliters of acetic anhydride. Heat the solution on a steam bath for one hour. Remove the ex cess acetic anhydride by evaporation in vacuo. Add 5 milliliters of methanol to the residual solution remaining after removal of the excess acetic anhydride. Evaporate the solution to dryness, leaving a residue. Dissolve the residue in hot methanol. Cool the solution with resultant precipitation. Filter and dry the first crop of solid precipitate weighing 4.3 grams and melting at 110.0-111.5 degrees Centigrade. Evaporate methanol from the filtrate l to concentrate the solution. Cool the solution with resultant precipitation of a second crop of product. Filter and dry the second crop of solid precipitate weighing- Percent Percent Percent carbon hydrogen chlorine Calculated 51. 74 V 5. 35 11.75 Found .52. 75 5. 61 11.7

Dissolve 3.02 grams of the above 1-chloro-2-(N-acetylcarbamyloxy)-3-(o-methoxyphenoxy)propaue in 9 milliliters of ethanol at 60 degrees centigrade. Cool the solution to 27 degrees oentigrade with the formation of a precipitate. While stirring the mixture, add 16 milliliters of 5 percent sodium hydroxide solution. The temperature rises to 40 degrees centigrade and the solution becomes almost clear momentarily. Soon a precipitate forms. Stir the mixture for two hours. Filter the precipitate to recover 1.85 grams of crude 5-(o-methoxyphenoxymethyl)2-oxazo1-idone, melting 'at 137-139 degrees centignade. Recrystallize samples from ethanol solvent to produce purer portions melting at 140-145 degrees centigrade.

EXAMPLE .3

Preparation of 5-(o-meth0xyphenoxymethyZ)-2-0xaz0lidone from 1-chloro-2-carbamyZoxy-3-(o-methoxyphenoxy propane then filter to recover 13.3 grams (74.5 percent yield) of crude 5-(o-rnethoxyphenoxymethyl) 2-oxazolidone, melting .at 136-139 degrees centigrade. Recrystallize to get product melting 140-145 degrees Centigrade.

EXAMPLE 4 Preparation of 5-(o-methoxyphenoxymethyl)-2-oxazolidone from a mixture of 1hydroxy-2-carbamyloxy-3- (o-methoxyphenoxy) propane and l -carbamyloxy-2-hydroxy-S- (o-methoxyphenoxy propane Mix 8.435 grams of l-carbamyloxy 2 hydroxy-3-(o- 'methoxyphenoxy) propane and 3.615 grams of I-hydroxy- 2-carbamyloXy-3-(o-methoxyphenoxy)propane in 50 milliliters of toluene at 25 degrees centigrade.

Add 6.5 grams of thlonyl chloride to the mixture. Warm the mixture to about 50 degrees centigrade and commence V bubbling dry air through the mixture to sweep out gases. Wh le continuing to bubble. air, raise the temperature of the mixture to about degrees centigrade and maintain this temperature for two hours. Thereafter, remove the toluene by distillation, leaving a residue. To the residue, add 5.6 grams of acetic anhydride and 0.1 gram of ptoluenesulfonic acid. Heat the mixture on a steam bath for one hour. Thereafter, while maintaining the mixture under reflux, add 20 milliliters of ethanol into which the mixture dissolves. Next, while maintaining the mixture at a temperature of .70 degrees centigrade, add milliliters of sodium hydroxide thereto. Precipitation of a solid begins shortly after the addition of sodium hydroxide is completed. Stir and cool the mixture for one hour. Filter the mixture to recover 8.0 grams of solid crude 5-(o-methoxyphenoxymethyl)-2-oxazolidone, meltat 137-140 degrees centigrade.

EXAMPLE 5 Production of intermediate 1-chloro-2-(N-acetylcarbamyloxy) 3 (o-chlorophenoxy) propane and 5-(o-clzl0rophenoxymethyl)-2-0xazolidone.

the mixture to distill off the alcohol formed by the reaction through a fractionating column. After the theoretical quantity of alcohol has distilled ofi, add 3.0 grams of ammonium chloride to the mixture to destroy the sodium methylate catalyst and arrest further reaction.

While stirring the aqueous solution,

Carbon Hydrogen Calculated 52. 52 3. 93 Found 53.15 3. 96

Next, the 4-(o-chlorophenoxymethyl)dioxolone is ammonolyzed to a mixture of the isomers l-hydroxy-Z- carbamyloxy-3-(o-chlorophenoxy)propane and l-carbamyloxy-Z-hydrox 3-(o-chlorophenoxy) propane. Stir the crude 4-(o-chlorophenoxymethyl)dioxolone overnight with 1200 milliliters of isopropyl alcohol containing 34 grams (2 moles) of anhydrous ammonia. Heat the mixture to reflux in order to remove excess ammonia. Add charcoal and mix. Filter. Allow the filtrate to cool with resultant precipitation of a crude 1-carbamyloxy-2- hy-droxy-3-(o-chlorophenoxy)propane. Filter. Concentrate the filtrate and cool to obtain a second crop of this compound. Repeat the concentration and crystallization to obtain several further crops of crude l-carbamyloxy-2-hydroxy-3-(o-chlorophenoxy)propane. After several concentrations, evaporate the filtrate to dryness. Fractionally crystallize the residue remaining after evaporation from ethyl acetate solvent to obtain crystalline 1 hydroxy 2 carbamyloxy 3 (o-chlorophenoxy) propane. The total crystalline product obtained is 230 grams (94 percent yield).

The pure 1 carbamyloxy-Z-hydroxy-B-(o-chlorophenoxy)propane melts at 98.4-98.9 degree centigrade and has the following percentage analysis; based on an empirical formula of C H O CIN:

Carbon Hydrogen Nitrogen aleulated C 5. 70 Found Carbon Hydrogen Nitrogen Calculated Found The chlorination and rearrangement is next performed as follows: Stir 36.75 grams (0.15 mole) of l-carbamyloxy-2-hydroxy-3-(o-chlorophenoxy)propane in 150 milliliters of dry toluene. Add 195 grams of thionyl chloride. Slowly heat the mixture to reflux temperature. Maintain the temperature at about 110 degrees centigrade for 2 hours. Cool the mixture with the resultant formation of a voluminous precipitate. Filter the solid melting at 81-82 degrees Centigrade. Recrystallize the solid from isopropyl alcohol to obtain l-chloro-2-carbamyloxy- 3-(o-chlorophenoxy) propane melting at 81.2-82.0 degrees centigrade and having the following percentage analysis, based on an empirical formula of C l-l Cl No z Carbon Hydrogen Nitrogen Calculated Found Acylate and cyclize the 1-chloro-2-carbamyloxy-3-(ochlorophenoxy) propane as follows:

Mix 5.28 grams (0.02 mole) of the 1-chloro-2-carbamyloxy-Ii- (o-chlorophenoxy) propane with 0.03 gram of zinc chloride and 2.3 grams of acetic anhydride in a reaction flask. Place an oil bath around the reaction flask. Heat the oil bath to a temperature of 100-120 degrees centigrade for three hours. A hard paste forms in the reaction flask. Crystallize the paste from a solvent mixture of ethanol and water to obtain crystals melting at 66.5-69.0 degrees Centigrade. Recrystallize from pentane solvent to obtain 1-cl1loro-2-(N-acetylcarbamyloxy)-3-(ochlorophenoxy)propane melting at 69.7-70.2 degrees centigrade, having the following percentage analysis, based on an empirical formula of C H Cl NO Carbon Hydrogen Nitrogen.

Calculated 47. 08 4. 38 4. 57 Found 46. 4. 0O 4. 61

EXAMPLE 6 Production of intermediate .Z-chl0r0-2-(N-acetylcarbamyloxy)-3-(0-methylphen0xy)propane and 5-(0-methylphenoxymethyl) -2-0xaz0lidone Prepare the starting material, l-chloro-Z-carbamyloxy- 3-(o-methylphenoxy)propane, as follows: React diethyl carbonate with 3-(o-methylphenoxy)-1,2-propanediol to produce 4-(o-methylphenoxymethyl)-2-dioxolone, melting at 95.4-96.0 degrees Centigrade. See Ludwig et al., Journal of the American Chemical Society, volume 73, page 5894. Then ammonolyze the 4-(o-methylpl1enoxymethyl)-2-dioxolone with ammonia to produce a mixture of l-hydroxy 2 carbamyloXy-Zi- (o-methylphenoxy)propane melting at 115.0-115.6 degrees centigrade and 1- carbamyloxy 2 hydroxy 3 (0 methylphenoxy)pro pane melting at 92.0-93.0 degrees centigrade. The latter compound was prepared by Yale et al., Journal of the American Chemical Society, volume 72, page 3715. Separate the isomers by fractional crystallization.

Mix one part by weight of the l-carbamyloxy-Z-hydroxy-3-(o-methylphenoxy)propane with a molar excess of thionyl chloride in toluene solvent. Heat the mixture to reflux and continue heating until the evolution of hydrogenchloride and sulfur dioxide gases ceases. Bubble dry air through the reaction mixture to sweep out the gases. Cool the mixture and recover, using procedures as set forth in the previous examples, 1-chloro-2-carbamyloXy-S-(o-methylphenoxy)propane, melting at 87.2-88.0 degrees centigrade and having the following percentage analysis, based on an empirical formula of C H ClNo z Acylate the 1-chloro-2-carbamyloxy-3-(o-methylphenoxy) propane as follows: Mix one part of the l-chloro-Z- carbamyloxy-S-(o-methylphenoxy)propane with a molar excess of acetic anhydride and a quantity of zinc chloride. Heat the mixture for several hours. Recover 1-chloro-2 (N-acetyl-carbamyloxy) 3 (o-methylphenoxy)propane,

EXAMPLE 7 7 Production of intermediate 1-chlor0-2(N-acetylcarbamyloxy -3a(2-naphthyloxy propane and 5 -(2-naphthy loxymethyl) -2-0xaz0lid0ne' 7 Prepare the starting material, 1-chloro-2-carbamyloxy- 3-(2-naphthyloxy) propane, ,as follows: React diethyl carbonate with 3-(2-naphthyloxy)-l,2-propanediol in a manner similar to that set forth in the preceding example, to produce 4-!(2-naphthyloxymethyl)-2-dioxolone, melting at 127.0.127.5 degrees centigrade. 'I'hen ammonolyze this 4-(2-naphthyloxymethyl)-2-dioxolone EXAMPLE 8 Production of intermediate 1-chl0r0-2-(N-propionylcarbamyloxy)-3-(2-naphthyloxy)propane and 5-(2- naphthyloxymerhyl -2-oxaz0lidone Mix 5.59 grams (0.02 mole) of l-chloro-Z-carbamyloxy-3-(2-naphthyloxy)propane with 3.25 grams (0.025 mole) of propionic anhydride and 0.15 gram of p-toluenesulf-onic acid. in :a reaction flask. Place an oil bath with ammonia to produce a mixture of 1-hydr0xy 2- carbamyloxy 3 '(2 naphthyl-oxy) propane melting rat 150. 815'1.0 degrees centigrlade and l-carbamyloxy-Z- hydroxy-3-(2-naphthyloxy)propane melting at 144.5- 145.0 degrees centigrade. Separate the isomers by fractional crystallization. V

'lVlix one part by Weight of the l-carbamyloxy-Z-hy- -droXy-3a(2-naphthyl-oxy) propane with a molar excess of thionyl chloride in toluene solvent. Heat the mixture to reflux and continue heating until the evolution of hydrogen chloride and sulfur dioxide gases ceases. Bubble dry air through the reaction mixture to sweep out the gases. Cool the mixture and recover using procedures as set forth in the previous examples, l-chloro- 2 carbamyloxy 3 (2 naphthyloxy)propane melting at 125.5-l26.0' degrees centigrade having the tollowing percentage analysis, based on an empirical formula of CmHmOlNOg I 7 Carbon Hydrogen Nitrogen Chlorine Calculated so. 11 s. 05 5. 01 i 12. 67 Found 60. 05 5. 01 4. 45 12. 05

. 3-(2-naphthyloxy)propane melting at 1-10.5111.0 degrees centigrade and having the following percentage analysis, based on an empirical formula of C H CINO Carbon Hydrogen Nitrogen Calculated 59. 72 5. 01 4. 35 Found 60. 02 6.22 4. 50

To cyclize, dissolve the l-chloro-Z (N-acetylcarbamyh oxy)-3-(2-nap=hthyloxy) propane in acetone and treat the solution with 10 percent aqueous sodium hydroxide solution to obtain 5-(2-naphthyloxyrnethyl)-2-oxazolidone,

melting at 1932-1936 degrees centigrade and having the following percentage analysis, based on an empirical formula of C H NO Carbon .Hydrogen Nitrogen Calculated 69. 12 5. 38 6. 75 Found 69. 28 5. 27 5. 45

around the reaction flask. Heat the oil bath to .a tem penature of 100410 degrees centigrade for 3 hours. Dilute the hot solution with milliliters of dry methanol. Heat the solution to reflux and then cool. Crystals precipitate. Filter to obtain 5.0 grams (70 percent yield) of crude crystals, melting at 136.5-137.5 degrees centigrade. Recrystallize the crude crystals from methanol solvent to obtain 1-chloro-2-(N-propionylcarbamyl- 'oxy)-3-(2-naphthyloxy)propane, melting =at 137.4-137.8 degrees centigrade and having the following percentage analysis, based on an empirical formula of C I-1 N60 Carbon Hydrogen Nitrogen Calculated 60.81 5. 40 4.17 Found 60. 29 5. 48 4. 03

Dissolve the 1 chloro 2 (N propionylcarbamyloxy)-3 (2-naphthyl-oxy)propane in acetone and treat'the solution with dilute sodium hydroxide. Recrystallize the product obtained from the ethanol solvent to obtain 5 (2 naphthyloxymethyl) 2 oxazolidone, melting at 1930-1936 degrees centigrade.

The invention can be embodied in other specific forms with-out departing from the spirit or essential characteristics thereof. The foregoing physical embodiments are therefore to be considered in all respects illustrative and not restrictive; The scope of the invention is indicated by the subjoined claims rather than by the foregoing description. All changes which come Within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Having described my invention, I claim:

.1.' 1 halo 2 (N :acylcarbamyloxy) 3 substituted propanes Whereinacyl is the 2103 1 radical of :an alkanoic acid containing from one to ten carbon atoms, inclusive, and wherein the 3-substituent is an aryloxy radical of the benzene and naphthalene series, any substituents on the aryl group being selected from the group consisting :of 'l-owenalkyl, lower alkoxy, halo, nitro, amino and trifiuo-romethyl.

2. l chlorc 2 (N :acylearbamyloxy) 3 substi- .tuted propanes wherein acyl is thewacyl radical of an .ialkanoic acid containing from one to ten carbon atoms,

inclusive, and wherein the S-su-bstit-uent is an aryloxy radical of the benzene and naphthalene series, any substituents on the aryl group being selected from the group consisting of loWer-alkyl, lower-:alkoxy, halo, nitro, amino and trifiuoromethyl.

3. 1 chloro 2 (N acetyloarbamyloxy) 3 (omethoxyphenoxy) propane.

. 4. 1 chloro 2 (N acetylcarbamyloxy) 3 (onrethylphenoxy) propane.

5. 1 chloro 2 (N acetylcarbamyloxy) chloroplrrenoxy)rpropa'ne.

6. 1 chloro 2 (N acetylcarbamyloxy) 3 (2- naphthyloxy) propane.

7. 1 chloro 2 (N propionylcarbamyloxy) 3 (2- naphthyloxy)propane.

References Cited by the Examiner UNITED sTATEs PATENTS 3,042,711 7/62 Clark 260-482 LORRAINE A. WEINBERGER, Primary Examiner. LEON ZI'IVER, Examiner. 

1. 1 - HALO - 2 (N - ACYLCARBAMYLOXY) - 3 - SUBSTITUTED PROPANES WHEREIN ACYL IS THE ACYL RADICAL OF AN ALKANOIC ACID CONTAINING FROM ONE TO TEN CARBON ATOMS, INCLUSIVE, AND WHEREIN THE 3-SUBSTITUENT IS AN ARYLOXY RADICAL OF THE BENZENE AND NAPHTHALENE SERIES, ANY SUBSTITUENTS ON THE ARYL GROUP BEING SELECTED FROM THE GROUP CONSISTING OF LOWER-ALKYL, LOWER-ALKOXY, HALO NITRO, AMINO AND TRIFLUORMETHYL. 